DESCRIPTION: The PI has recently discovered a method for the high precision combinatorial determination of small isotope effects at natural abundance. Compared to conventional methods for measuring isotope effects, the methodology is 1-2 orders of magnitude faster, is much more versatile, provides much greater information, and is more reliably accurate. Based on this discovery it is proposed here to study the mechanisms of a series of important organic and bioorganic reactions. These include the TMSCl-mediated addition of cuprates to enones, the Sharpless asymmetric dihydroxylation, ozonolysis, the enzymatic cyclization of squalene oxide, ene reactions and many others. The unique capabilities of the methodology should significantly advance mechanistic understanding of these reactions. The health-relatedness of this work derives from its impact on the understanding of reactions important in the synthesis of medicinally important substances, and reactions centrally important in biosynthetic pathways. Another objective is to extend the methodology to the determination of binding isotope effects. A detailed analysis of the impact of small isotope effects on chromatographic separations suggests that their ultra-high precision determination should be possible by NMR analysis after chromatographic separation. The precise isotope effects obtained should provide tremendous information on molecule-molecule or molecule-surface interactions. The goal is to develop practical methodology for the general study of binding isotope effects, and develop the use of this methodology in studying molecule-molecule binding interactions.